Process for the preparation of asymmetrical bis(thiosemicarbazones)

Abstract

The present invention relates to a method of making asymmetrical bis(thiosemicarbazones), compounds useful as synthetic intermediates in the method, new bis(thiosemicarbazones) that can be readily accessed by use of the method and methods of treatment and imaging utilising some of the new bis(thiosemicarbazones).

1 .- 41 . (canceled) 
     
     
         42 . A method of making a compound of the formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 6 -C 18 aryl, and optionally substituted C 1 -C 18 heteroaryl 
         wherein R 4  is a group of the formula:
   —X—Y
 
 
       
       wherein X is selected from the group consisting of:
 (a) a bond 
 (b) —(CH 2 ) m CO 2 — 
 (c) —(CH 2 ) m CO— 
 (d) —(CH 2 ) m SO 3 — 
 (e) —(CH 2 ) m SO 2 — 
 (f) —(CH 2 ) m R 8 — 
 (g) —(CH 2 ) m CHR 9 R 10    
 (h) —(CH 2 ) m NHCO 2 — 
 (i) —(CH 2 ) m NH— 
 (j) —(CH 2 ) m NR 9 — 
 (k) —(CH 2 ) m NHSO 2 — 
 (l) —(CH 2 ) m SO 2 — 
 (m) —(CH 2 ) m SO 3 — 
 (n) —(CH 2 ) m R 8 — 
 (o) —(CH 2 ) m CHR 9 R 10 ; 
 (p) —((CH 2 ) x O) y —; 
 (q) —((CH 2 ) x NR 11 ) y —; 
 wherein m is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; 
 each x is independently an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; 
 y is an integer selected from the group consisting of 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; 
 R 8  is selected from the group consisting of optionally substituted C 6 -C 18 aryl, and optionally substituted C 1 -C 18 heteroaryl, 
 each R 9  and R 10  is independently selected from the group consisting of CO 2 H, optionally substituted C 1 -C 12 alkyl, and optionally substituted C 2 -C 12 heteroalkyl; 
 R 11  is independently selected from the group consisting of H, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 heteroalkyl and a nitrogen protecting group; 
 Y is selected from the group consisting of H, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 12 heteroalkyl, optionally substituted C 3 -C 9 cycloalkyl, optionally substituted C 3 -C 9 cycloalkenyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 2 -C 12 heterocycloalkenyl, optionally substituted C 6 -C 18 aryl, optionally substituted C 1 -C 18 heteroaryl, optionally substituted C 3 -C 9 cycloalkylC 1 -C 2 alkyl, C 2 -C 12 heterocycloalkylC 1 -C 12 alkyl, optionally substituted C 6 -C 18 arylC 1 -C 12 alkyl, optionally substituted C 1 -C 18 heteroarylC 1 -C 12  alkyl, optionally substituted C 6 -C 18 arylC 2 -C 12 heteroalky, optionally substituted C 3 -C 9 cycloalkylC 2 -C 12 heteroalkyl, optionally substituted C 6 -C 18 arylC 2 -C 12 heteroalkyl, optionally substituted C 2 -C 12 heterocycloalkylC 2 -C 12 heteroalkyl, optionally substituted C 1 -C 18 heteroaryl C 2 -C 12 heteroalkyl, a peptide, a protein and a molecular recognition moiety, 
 such that R 1  and R 4  are not the same; 
 R 2  and R 3  are each independently selected from the group consisting of: H, optionally substituted C 1 -C 12 alkyl, optionally substituted C 2 -C 12 alkenyl, optionally substituted C 2 -C 12 alkynyl, optionally substituted C 2 -C 12 heteroalkyl, optionally substituted C 3 -C 12 cycloalkyl, optionally substituted C 2 -C 12 heterocycloalkyl, optionally substituted C 6 -C 18 aryl, and optionally substituted C 1 -C 18 heteroaryl, 
 or R 2  and R 3  when taken together with the carbon atoms to which they are attached form an optionally substituted C 3 -C 12 cycloalkyl group; 
 the method comprising reacting a compound of formula (II) 
 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2 , and R 3  are as defined above and R 5  and R 6  are non hydrogen substituent groups with a primary amine of formula (III) NH 2 R 4 . 
     
     
         43 . A method according to  claim 42 , wherein R 2  and R 3  are each independently selected from the group consisting of H and optionally substituted C 1 -C 12 alkyl. 
     
     
         44 . A method according to  claim 42 , wherein R 5  and R 6  each independently an optionally substituted C 1 -C 12 alkyl. 
     
     
         45 . A method according to  claim 42 , wherein R 4  is selected from the group consisting of optionally substituted C 1 -C 12  alkyl, optionally substituted C 2 -C 12  alkenyl, optionally substituted C 2 -C 12  alkynyl, optionally substituted C 2 -C 12  heteroalkyl; optionally substituted C 3 -C 9  cycloalkyl, optionally substituted C 3 -C 9  cycloalkenyl, optionally substituted C 2 -C 12  heterocycloalkyl, optionally substituted C 2 -C 12  heterocycloalkenyl, optionally substituted C 6 -C 18  aryl, optionally substituted C 1 -C 18  heteroaryl, optionally substituted C 3 -C 9  cycloalkyl C 1 -C 12  alkyl, C 2 -C 12  heterocycloalkyl C 1 -C 12 alkyl, optionally substituted C 6 -C 18  aryl C 1 -C 12  alkyl, optionally substituted C 1 -C 18  heteroaryl C 1 -C 12  alkyl, optionally substituted C 6 -C 18  aryl C 2 -C 12  heteroalkyl, optionally substituted C 3 -C 9  cycloalkyl C 2 -C 12  heteroalkyl, optionally substituted C 6 -C 18  aryl C 2 -C 12  heteroalkyl, optionally substituted C 2 -C 12  heterocycloalkyl C 2 -C 12  heteroalkyl, and optionally substituted C 1 -C 18  heteroaryl C 2 -C 12  heteroalkyl. 
     
     
         46 . A method according to  claim 45 , wherein Y is H or a molecular recognition moiety. 
     
     
         47 . A method according to  claim 42 , wherein R 5  is methyl. 
     
     
         48 . A method according to  claim 42 , wherein R 6  is methyl. 
     
     
         49 . A method according to  claim 42 , wherein the compound of formula (1) is selected from the group consisting of: